Skeletal muscle atrophy represents an enormous unmet medical need in Veteran patients. Frequent causes of skeletal muscle atrophy include orthopedic injuries, bed rest, advanced age, cancer, heart failure, COPD, diabetes, stroke, renal failure, critical illness and spinal cord injuy. Effects of skeletal muscle atrophy include weakness, reduced activity, falls, fractures, debilitation, prolonged hospitalization and rehabilitation, nursing home placement, and increased mortality. Although skeletal muscle atrophy has broad clinical impact in the Veteran population, a pharmacologic therapy for muscle atrophy does not exist, and current therapeutic approaches (nutrition and physical rehabilitation) are often ineffective and/or unfeasible. Our long-term goal is to develop a pharmacologic therapy for skeletal muscle atrophy. In preliminary studies, we studied human subjects to determine mRNA expression signatures of human skeletal muscle atrophy, and then used these signatures in conjunction with a novel drug discovery method to identify two small molecules (ursolic acid and compound A) as predicted pharmacologic inhibitors of human skeletal muscle atrophy. Using mouse models, we found that ursolic acid and compound A prevent and reverse skeletal muscle atrophy, increase muscle strength, and improve exercise capacity. In addition to these effects in mice, we found that ursolic acid and compound A stimulate growth of human skeletal myotubes, an in vitro model of human skeletal muscle. Importantly, data from us and others suggest that ursolic acid and compound A have favorable safety profiles, suggesting good potential for translation to Veteran patients. Although these data identify ursolic acid and compound A as exciting potential therapeutic agents to prevent and reverse skeletal muscle atrophy in Veteran patients, some critical questions remain unanswered. For example, we do not yet understand how ursolic acid and compound A reduce muscle atrophy and improve muscle function. In addition, ursolic acid and compound A are structurally dissimilar and exhibit some differences in their physiological and biochemical effects, suggesting that the combination of ursolic acid and compound A could be more beneficial than either compound alone. To determine mechanisms of action and potential for combination therapy, we propose two aims. In Specific Aim 1, we will use human skeletal myotubes to determine cellular mechanisms that ursolic acid and compound A utilize to increase muscle mass and improve muscle function. Since skeletal muscle mass and function are tightly linked to skeletal muscle protein, mitochondria and anabolic signaling, we will test th hypotheses that ursolic acid and compound A increase the net balance of protein synthesis to protein degradation, increase mitochondrial mass and respiration, and stimulate anabolic signaling. Collectively, these studies will provide an important mechanistic foundation for clinica studies of ursolic acid and compound A in patients with skeletal muscle atrophy. In Specific Aim 2, we will use mouse models to determine if the combination of ursolic acid and compound A is more beneficial than either compound alone. We will test the hypotheses that the combination of ursolic acid and compound A prevents and reverses skeletal muscle atrophy, increases strength, and improves exercise capacity more than either compound alone. If the combination of ursolic acid and compound A demonstrates additional benefit in muscle atrophy, combination therapy would be carried forward to clinical studies. Through these studies, we hope to develop new therapeutic agents for skeletal muscle atrophy, and quality of life of many Veteran patients. a common and debilitating condition that diminishes the health